Multiple sclerosis (MS) is a chronic, neurological, autoimmune, demyelinating disease. MS can cause blurred vision, unilateral vision loss (optic neuritis), loss of balance, poor coordination, slurred speech, tremors, numbness, extreme fatigue, changes in intellectual function (such as memory and concentration), muscular weakness, paresthesias, and blindness. Many subjects develop chronic progressive disabilities, but long periods of clinical stability may interrupt periods of deterioration. Neurological deficits may be permanent or evanescent. In the United States there are about 250,000 to 400,000 persons with MS, and every week about 200 new cases are diagnosed. Worldwide, MS may affect 2.5 million individuals. Because it is not contagious, which would require U.S. physicians to report new cases, and because symptoms can be difficult to detect, the incidence of disease is only estimated and the actual number of persons with MS could be much higher.
The pathology of MS is characterized by an abnormal immune response directed against the central nervous system. In particular, T-lymphocytes reactive against myelin antigens are believed to initiate an inflammatory response within the central nervous system (CNS). The resultant inflammatory response includes recruited T-lymphocytes, activated macrophages, B-lymphocytes and plasma cells. Soluble mediators released by these inflammatory cells result in demyelination and, to a lesser extent, axonal degeneration. Areas within the CNS in which demyelination and axonal injury have occurred develop an astrocytic scar and these scarred or “sclerotic” areas are referred to as plaques. These lesions appear in scattered locations throughout the brain, optic nerve, and spinal cord. Most subjects recover clinically from individual bouts of demyelination, producing the classic remitting and exacerbating course of the most common form of the disease known as relapsing-remitting multiple sclerosis. Many patients eventually enter a progressive phase of disease, referred to as secondary progressive MS, in which they worsen continually. Some patients do not start with a relapsing-remitting course but have progressive disease from onset; this is referred to as primary progressive MS. In both forms of progressive MS, a progressive degeneration of axons is believed to cause the continuous loss of function.
The status of MS patients can be evaluated by longitudinal, monthly follow-up of magnetic resonance (MRI) activity in the brain of MS patients. MRI offers a unique set of outcome measures for phase I/II clinical trials in small cohorts of patients, and is thus well suited to establish data for proof of principle for novel therapeutic strategies (e.g., see Harris et al., Ann. Neurol. 29:548-555, 1991; MacFarland et al., Ann. Neurol. 32:758-766, 1992; Stone et al., Ann. Neurol. 37:611-619, 1995). There are currently six FDA-approved treatments for MS, three types of IFN-β (the Interferon-B multiple sclerosis study group, Neurology 43:655-661, 1993; the IFNB Multiple Sclerosis Study Group; and the University of British Columbia MS/MRI Analysis Group, Neurology 45:1277-1285, 1995; Jacobs et al., Ann. Neurol. 39:285-294, 1996), a random polymer of four amino acids (glatiramer acetate) (Johnson K P, Group. tCMST, J. Neurol. 242:S38, 1995), a chemotherapy drug (mitoxantrone) (Hartung et al. Lancet 360:2018-2025, 2003), and a humanized monoclonal antibody, natalizumab, directed against alpha4-integrin (O'Connor et al., Neurology 62:2038-2043, 2004 and U.S. Pat. Nos. 6,033,665 and 5,840,299, incorporated herein by reference).
Current therapeutic interventions for MS depend exclusively on modulators of the immune/inflammatory response during disease progression. Cyclosporin A (CsA) is an 11 amino acid cyclic peptide of fungal origin that is currently used clinically as an immunosuppressant due to its inhibition of the protein phosphatase calcineurin. CsA has been shown to reduce tissue injury in experimental autoimmune encephalomyelitis (EAE). However, the toxicity associated with long term CsA use has prevented its use as a treatment for MS. Thus, a need remains for additional agents for treatment of MS.